Article ; Online: Crystal structure of the CoV-Y domain of SARS-CoV-2 nonstructural protein 3.
2023 Volume 13, Issue 1, Page(s) 2890
Abstract: Replication of the coronavirus genome starts with the formation of viral RNA-containing double-membrane vesicles (DMV) following viral entry into the host cell. The multi-domain nonstructural protein 3 (nsp3) is the largest protein encoded by the known ... ...
Abstract | Replication of the coronavirus genome starts with the formation of viral RNA-containing double-membrane vesicles (DMV) following viral entry into the host cell. The multi-domain nonstructural protein 3 (nsp3) is the largest protein encoded by the known coronavirus genome and serves as a central component of the viral replication and transcription machinery. Previous studies demonstrated that the highly-conserved C-terminal region of nsp3 is essential for subcellular membrane rearrangement, yet the underlying mechanisms remain elusive. Here we report the crystal structure of the CoV-Y domain, the most C-terminal domain of the SARS-CoV-2 nsp3, at 2.4 Å-resolution. CoV-Y adopts a previously uncharacterized V-shaped fold featuring three distinct subdomains. Sequence alignment and structure prediction suggest that this fold is likely shared by the CoV-Y domains from closely related nsp3 homologs. NMR-based fragment screening combined with molecular docking identifies surface cavities in CoV-Y for interaction with potential ligands and other nsps. These studies provide the first structural view on a complete nsp3 CoV-Y domain, and the molecular framework for understanding the architecture, assembly and function of the nsp3 C-terminal domains in coronavirus replication. Our work illuminates nsp3 as a potential target for therapeutic interventions to aid in the on-going battle against the COVID-19 pandemic and diseases caused by other coronaviruses. |
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MeSH term(s) | Humans ; SARS-CoV-2/metabolism ; Molecular Docking Simulation ; Pandemics ; COVID-19 ; Protein Domains ; Viral Nonstructural Proteins/genetics |
Chemical Substances | Viral Nonstructural Proteins |
Language | English |
Publishing date | 2023-02-18 |
Publishing country | England |
Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. |
ZDB-ID | 2615211-3 |
ISSN | 2045-2322 ; 2045-2322 |
ISSN (online) | 2045-2322 |
ISSN | 2045-2322 |
DOI | 10.1038/s41598-023-30045-9 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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